A study to see if a new generic form of primaquine is the same as the one currently on the market
| ISRCTN | ISRCTN54640699 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN54640699 |
| Secondary identifying numbers | Protocol No. C1B00842, MORU Ref No. MAL21010 |
- Submission date
- 22/10/2021
- Registration date
- 11/11/2021
- Last edited
- 11/06/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Other
Plain English Summary
Background and study aims
Primaquine (PQ) or PQ phosphate is a drug that was developed in the 1950s by the US army that is used to prevent relapse in Plasmodium vivax and P. ovale malaria and has been recommended for many years by the WHO for blocking the transmission of P. falciparum malaria.
There is now a growing interest in single low-dose PQ for blocking the transmission of Plasmodium falciparum, following the WHO’s recommendation in 2012. WHO recommends the use of a single 0.25-mg/kg dose of PQ in combination with standard artemisinin-based combination therapy (ACT) for the treatment of P. falciparum malaria in elimination and resistance containment settings. Several trials have shown that single low-dose primaquine reduced mosquito infectivity.
Children are disproportionally affected by malaria of which vivax malaria affects young children less than 15 years of age, peaking between 2 and 6 years, which carries the highest risk of illness and death. Children under the age of 5 years accounted for 67% of deaths from malaria in the African region in 2019.
However, there are no paediatric PQ formulations that are friendly to children. The availability of paediatric drugs in the right dosage forms with acceptable taste and odour/flavour is critically important for increasing adherence and allowing PQ regimens that do not need tablet fractions or require crushing tablets.
PQ is now considered essential for eliminating malaria but to ensure child-friendly PQ is made available it either has to be WHO prequalified or registered with a stringent drug regulatory authority.
WHO prequalification offers the possibility of a line extension based on demonstrating proportionality with the adult 15 mg tablet. For a generic manufacturer, a bioequivalence study must be performed comparing the generic (test) product with the reference 15 mg of primaquine.
This study is to establish the bioequivalence of a new scored 15 mg generic PQ tablet, produced by IPCA in India. The study will be conducted to international standards, following WHO guidelines and other applicable requirements.
Who can participate?
Healthy volunteers aged 18-45 years old inclusive
What does the study involve?
A single dose of the test and the reference products, both corresponding to primaquine 15 mg, is given to healthy volunteers under fasting conditions in two consecutive periods with a break of at least 10 days. Vitals signs and well-being will be monitored and blood samples will be collected at specific timepoints.
What are the possible benefits and risks of participating?
Participation in this study will yield no direct benefits to the participants. The risks as mentioned below are minimized as only a single dose is given in each period with an appropriate break between treatment periods. The adverse events are nausea, vomiting, epigastric (upper abdomen) distress, abdominal cramps, leukopenia (low white blood cells), hemolytic anemia (low red blood cells) in G6PD-deficient individuals, and methemoglobinemia in NADH methaemoglobin reductase deficient individuals, cardiac arrhythmia (abnormal heart rhythm) and QT interval prolongation, dizziness, rash and pruritus (itching).
Blood taking causes discomfort but this tends to be brief. Rarely, the sampling site may become infected. Full aseptic techniques will be used when taking blood to minimise the infection risk. The volume of blood taken is very small and not a health threat.
There are no direct short term benefits to the community. If the researchers are able to eventually make paediatric primaquine available, people in malaria-endemic countries will benefit.
Where is the study run from?
Cliantha Research Limited (India)
When is the study starting and how long is it expected to run for?
May 2021 to May 2023
Who is funding the study?
Medical Research Council (UK)
Who is the main contact?
Dr Bob Taylor
bob@tropmedres.ac
Contact information
Scientific
Mahidol Oxford Tropical Medicine Research Unit
Faculty of Tropical Medicine, Mahidol University
3/F, 60th Anniversary Chalermprakiat Building
420/6 Rajvithi Road
Bangkok
10400
Thailand
 ORCID ID |
0000-0001-6236-0464 |
|---|---|
| Phone | +662 (0)203 6333 |
| bob@tropmedres.ac |
Public
Mahidol Oxford Tropical Medicine Research Unit
Faculty of Tropical Medicine, Mahidol University
3/F, 60th Anniversary Chalermprakiat Building
420/6 Rajvithi Road
Bangkok
10400
Thailand
| Phone | +662 (0)203 6333 |
|---|---|
| bob@tropmedres.ac |
Study information
| Study design | Open-label randomized two-period two-treatment two-sequence crossover balanced single-dose oral bioequivalence study |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised cross over trial |
| Study setting(s) | Other |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use contact details to request a participant information sheet |
| Scientific title | Single-dose oral bioequivalence study of primaquine phosphate tablets USP 15 mg (test) and primaquine 15 mg tablet (reference) in healthy adult human subjects under fasting conditions |
| Study acronym | BE_PRIM |
| Study hypothesis | Primaquine phosphate tablets USP 15 mg (test) has equivalence bioavailability to primaquine 15 mg tablet (reference). The objectives of this study are: 1. To compare and evaluate the oral bioavailability of primaquine phosphate tablets USP 15 mg of IPCA with that of primaquine 15 mg tablet of Sanofi in healthy, adult, human subjects under fasting conditions. 2. To monitor the safety and tolerability of the subjects. |
| Ethics approval(s) | 1. Approved 27/04/2022, Oxford Tropical Research Ethics Committee (OxTREC; University of Oxford Research Services, University Offices, Wellington Square, Oxford OX1 2JD, UK; +44 (0) 1865 282585; oxtrec@admin.ox.ac.uk), ref: 40-21 2. Approved 21/10/2022, IBIOME – IEC (B- 01, Krishna Complex, Near Rajpath Club, S. G. Highway, Bodakdev, Ahmedabad – 380 054, Gujarat – India, +91-97244 05402; ibiomeiec@gmail.com), ref: C1B00842 |
| Condition | Bioequivalence study |
| Intervention | The following visits will be performed: 1. Screening phase: between Day -28 and Day -2 2. Interventional phase: Period 1: Day -1 to 3 Wash-out interval of at least 10 days Period 2: Day -1 to 3 A single dose of the test product (primaquine phosphate tablets USP 15 mg [IPCA]) and reference product (primaquine 15 mg tablet [Sanofi]) will be administered orally to the healthy male and female subjects under fasting conditions in two study periods as per the randomization schedule (TR or RT), generated by using SAS® statistical software, with a washout interval of at least 10 days between consecutive administration. Both test and reference products will be orally administered, swallowed whole with about 240 ml of water at ambient temperature, on the morning of study Day 0. The first subject will be started at approximately 09:00 AM. This activity will be followed by a mouth and hand check of the subjects to assess compliance to dosing. Vital signs and well-being assessment will be performed and blood samples for pharmacokinetic analysis will be collected at pre-dose (0.0 hour) and at 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.333, 2.667, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0, 10.0, 12.0, 16.0, 24.0, 36.0, 48.0 and 72.0 hours post-dose in each period. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase I |
| Drug / device / biological / vaccine name(s) | Primaquine |
| Primary outcome measure | The bioequivalent rate (Cmax) and extent (AUCt) of absorption of primaquine (plasma concentrations evaluated using LCMS/MS assay) after single dose administration of test and reference products, measured using samples collected at pre-dose (0.0 hour) and at 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.333, 2.667, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0, 10.0, 12.0, 16.0, 24.0, 36.0, 48.0 and 72.0 hours in each period of this cross over study |
| Secondary outcome measures | 1. The plasma PK profile of primaquine measured after single-dose administration of the test and reference products, measured using using LCMS/MS on samples collected at pre-dose (0.0 hour) and at 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.333, 2.667, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0, 10.0, 12.0, 16.0, 24.0, 36.0, and 48.0 hours in each period of this cross over study 2. The plasma PK profile of carboxyprimaquine after single-dose administration of the test and reference products (supportive data), measured using LCMS/MS on samples collected at pre-dose (0.0 hour) and at 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.333, 2.667, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0, 10.0, 12.0, 16.0, 24.0, 36.0, 48.0 and 72.0 hours in each period of this cross over study 3. Safety and tolerability of subjects after single-dose administration of the test and reference products, assessed by measuring the full blood count and routine biochemistry on the first day of each dosing cycle |
| Overall study start date | 01/05/2021 |
| Overall study end date | 01/05/2023 |
Eligibility
| Participant type(s) | Healthy volunteer |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Upper age limit | 45 Years |
| Sex | Both |
| Target number of participants | 50 |
| Total final enrolment | 50 |
| Participant inclusion criteria | 1. Age 18 to 45 years old, both inclusive 2. Male or non-pregnant, non-lactating female 2.1. Female of childbearing potential must have a negative serum beta human chorionic gonadotropin (β-HCG) pregnancy test performed within 28 days prior to the first dosing day. They must be using an acceptable form of contraception. 2.2. For females of childbearing potential, acceptable forms of contraception include the following: 2.2.1. Non-hormonal intrauterine device in place for at least 3 months prior to the start of the study and remaining in place during the study period, or 2.2.2. Barrier methods containing or used in conjunction with a spermicidal agent, or 2.2.3. Surgical sterilization or 2.2.4. Practicing sexual abstinence throughout the course of the study 2.3. Females will not be considered of childbearing potential if one of the following is reported and documented on the medical history: 2.3.1. Postmenopausal with spontaneous amenorrhea for at least 1 year, or 2.3.2. Bilateral oophorectomy with or without a hysterectomy and an absence of bleeding for at least 6 months, or 2.3.3. Total hysterectomy and an absence of bleeding for at least 3 months 3. BMI: 18.5 to 30.0 kg/m², both inclusive; BMI value should be rounded off to one significant digit after decimal point (e.g. 30.04 rounds down to 30.0, while 18.45 rounds up to 18.5) 4. Able to communicate effectively with study personnel 5. Willing to provide written informed consent to participate in the study 6. Non-smokers and non-tobacco users (i.e. having no past history of smoking and tobacco consumption for at least 1 year prior to the study) 7. All volunteers must be judged by the principal or sub-investigator or physician as normal and healthy during a pre-study safety assessment performed within 28 days of the first dose of study medication which will include: 7.1. A physical examination (clinical examination) with no clinically significant finding 7.2. Results within normal limits defined site normal range for the following tests: 7.2.1. Hematology: haemoglobin, total RBC count, total WBC count, platelet count, differential leukocyte count: neutrophils, lymphocytes, eosinophils, monocytes, basophils, blood indices: HCT, glucose-6-phosphate dehydrogenase (G6PD) 7.2.2. Biochemistry: BUN, serum creatinine, random glucose, SGPT & SGOT, alkaline phosphatase, uric acid, serum bilirubin, serum total protein: total proteins, albumin, serum electrolytes: serum sodium, serum chloride, serum potassium, serum phosphorous, serum calcium 7.2.3. Urinalysis: colour, quantity, specific gravity, odour, appearance, reaction, albumin, bilirubin, ketone bodies, sugar, urobilinogen and microscopical examination (performed based on clinical judgment) 7.2.4. Immunological tests: HIV-I & II, HBsAg, syphilis (RPR), anti HCV 7.2.5. Serum (β-HCG) pregnancy test (for females of childbearing potential) 7.2.6. Additional tests and/or examinations (apart from those mentioned in the protocol) may be performed, if necessary, based on the principal investigator's discretion 7.2.7. All results will be assessed against the current laboratory normal ranges at the time of testing and a copy of the normal ranges used will be included in the study documentation |
| Participant exclusion criteria | 1. History of allergic responses to primaquine or other related drugs, or any of its formulation ingredients 2. Have significant diseases or clinically significant abnormal findings during screening [medical history, physical examination (clinical examination), laboratory evaluations, ECG, chest X-ray recording, and, for females, gynaecological history 3. Any disease or condition like diabetes, psychosis or others, which might compromise the haemopoietic, gastrointestinal, renal, hepatic, cardiovascular, respiratory, central nervous system or any other body system 4. History or presence of bronchial asthma 5. Use of any hormone replacement therapy within 3 months prior to the first dose of study medication 6. A depot injection or implant of any drug within 3 months prior to the first dose of study medication 7. Use of CYP enzyme inhibitors or inducers within 30 days prior to the first dose of study medication (see http://medicine.iupui.edu/clinpharm/ddis/main-table) 8. History or evidence of drug dependence or of alcoholism or of moderate alcohol use 9. History of difficulty with donating blood or difficulty with the accessibility of veins 10. A positive hepatitis screen (includes subtypes B & C) 11. A positive test result for HIV antibody and/or syphilis (RPR) 12. Volunteers who have received a known investigational drug within seven elimination half-life of the administered drug prior to the first dose of study medication 13. Volunteers who have donated blood or lost blood: 50 ml to 100 ml within 30 days or 101 ml to 200 ml within 60 days or >200 ml within 90 days (excluding volume drawn at screening for this study) prior to the first dose of study medication, whichever is greater 14. History of difficulty in swallowing or of any gastrointestinal disease, which could affect drug absorption 15. Intolerance to venepuncture 16. Any food allergy, intolerance, restriction or special diet that, in the opinion of the principal investigator or sub-investigator, could contraindicate the volunteer’s participation in this study 17. Institutionalized volunteers 18. Use of any prescribed medications within 14 days prior to the first dose of study medication 19. Use of any OTC products, vitamin and herbal products, etc, within 7 days prior to the first dose of study medication 20. Use of grapefruit and grapefruit-containing products within 7 days prior to the first dose of study medication 21. Ingestion of any caffeine or xanthine products (i.e. coffee, tea, chocolate, and caffeine-containing sodas, colas, etc), recreational drugs, alcohol or other alcohol-containing products within 48 hours prior to the first dose of study medication 22. Ingestion of any unusual diet, for whatever reason (e.g. low sodium) for 3 weeks prior to the first dose of study medication 23. Volunteers with glucose-6-phosphate dehydrogenase (G6PD) deficiency 24. Volunteers with a family or personal history of hemolytic anemia |
| Recruitment start date | 14/12/2022 |
| Recruitment end date | 30/12/2022 |
Locations
Countries of recruitment
- India
Study participating centre
Sarkhej
Ahmedabad
Gujarat
382210
India
Sponsor information
University/education
Boundary Brook House
Churchill Drive
Headington
Oxford
OX3 7GB
England
United Kingdom
| Phone | +44 (0)1865 282585 |
|---|---|
| research.services@admin.ox.ac.uk | |
| Website | https://www.ox.ac.uk/ |
"ROR" |
https://ror.org/052gg0110 |
Funders
Funder type
Research council
Government organisation / National government
- Alternative name(s)
- Medical Research Council (United Kingdom), UK Medical Research Council, MRC
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 31/05/2025 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | The results will be published and authorship will follow international guidelines. |
| IPD sharing plan | Current IPD sharing plan as of 03/04/2024: The data from this study may be available upon receipt of a formal request and submission to the MORU Data Access Committee. Data cannot be shared until after we have obtained primaquine prequalification. Previous IPD sharing plan: Data will be shared according to the MORU data sharing policy on request from datasharing@tropmedres.ac. The data may be available in 2023. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol file | version 3.0 | 04/10/2022 | 01/03/2024 | No | No |
| Statistical Analysis Plan | version 3.0 | 04/10/2022 | 01/03/2024 | No | No |
| Other unpublished results | 23/05/2024 | 23/05/2024 | No | No | |
| Results article | 11/06/2024 | 11/06/2024 | Yes | No |
Additional files
Editorial Notes
11/06/2024: Publication reference added.
23/05/2024: A file of unpublished results was added.
03/04/2024: The intention to publish date was changed from 31/01/2024 to 31/05/2025. The IPD sharing plan was updated.
01/03/2024: Protocol (not peer reviewed) and statistical analysis plan added as additional files.
10/01/2023: Total final enrolment added.
20/12/2022: The following changes were made to the trial record:
1. The ethics approval was added.
2. The recruitment start date was changed from 28/12/2022 to 14/12/2022.
3. The recruitment end date was changed from 01/05/2023 to 30/12/2022.
4. The trial participating centre Cliantha Research Limited was changed to Cliantha Corporate.
08/12/2022: The following changes were made to the trial record:
1. The recruitment start date was changed from 15/12/2022 to 28/12/2022.
2. The recruitment end date was changed from 31/12/2022 to 01/05/2023.
3. The overall end date was changed from 31/01/2023 to 01/05/2023.
4. The plain English summary was updated to reflect these changes.
17/10/2022: The recruitment start date was changed from 01/10/2022 to 15/12/2022.
12/05/2022: The following changes have been made:
1. The ethics approval has been updated.
2. The overall trial end date has been changed from 01/10/2022 to 31/01/2023 and the plain English summary updated accordingly.
3. The recruitment start date has been changed from 01/05/2022 to 01/10/2022.
4. The recruitment end date has been changed from 31/08/2022 to 31/12/2022.
5. The sponsor contact details have been changed.
6. The intention to publish date has been changed from 01/10/2023 to 31/01/2024.
28/10/2021: Trial's existence confirmed by Oxford Tropical Research Ethics Committee.
